Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients

for the “OPTI-CLOT” study group

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Abstract

Aims: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. Methods: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03–15.2) and body weight of 14 kg (4–57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. Results: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL−1. Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03–77.6) and body weight of 30 kg (4–111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h−1 68 kg−1, 2930 mL 68 kg−1, 1810 mL 68 kg−1, and 172 mL h−1 68 kg−1, respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL−1. Conclusions: This study emphasizes the importance of external validation of population PK models using real-life data.

Original languageEnglish
Pages (from-to)4408-4420
Number of pages13
JournalBritish Journal of Clinical Pharmacology
Volume87
Issue number11
Early online date22 Apr 2021
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
M.C. has received grants from governmental research institutes, such as the Dutch Research Institute (NWO), ZonMW, Innovation fund, NWO‐NWA and unrestricted investigator‐initiated research grants as well as educational and travel funding from various companies over the years (Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis and Nordic Pharma), and has served as a member on steering boards of Roche and Bayer. All grants, awards and fees received go to the institution. F.L. received research support from CSL Behring and Shire/Takeda for performing the WiN study; is a consultant for uniQure, Novo Nordisk and Shire/Takeda, the fees of which go to the institution; and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. R.M. reports grants from Bayer, grants from Shire, grants from Merck Sharpe Dome, grants from CSL Behring, other from Bayer, other from Shire, outside the submitted work. The other authors declare no competing financial interests. K.F. reports grants from CSL Behring, grants from Novo Nordisk, other from Takeda, other from Roche, other from Pfizer, outside the submitted work. F.M. reports grants from CSL Behring, grants from Pfizer, grants from Bayer, grants from Novo Nordisk, grants from Sobi, grants from Roche, grants from Takeda, outside the submitted work. D.H. reports grants from Octapharma, grants from Grifols, grants from Takeda, personal fees and other from Biomarin, personal fees and other from Uniqure, personal fees and other from Sobi, personal fees and other from Sanofi, personal fees from NovoNordisk, personal fees and other from Pfizer, personal fees from BIotest, personal fees and other from Takeda, personal fees from Spark, personal fees from Roche, personal fees from Bayer, outside the submitted work. B.G. reports grants from Baxter, grants from CSL Behring, outside the submitted work. R.L. reports other from Octapharma, other from Octapharma, during the conduct of the study; other from SOBI, other from SOBI, outside the submitted work. All other authors declare that they have no conflict of interests.

Publisher Copyright:
© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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